Objective: To examine frequencies and relationships of 5 common neuropathologic abnormalities identified at autopsy with late-life cognitive impairment and dementia in 2 different autopsy panels. Methods:The Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS) are population-based investigations of brain aging that included repeated cognitive assessments and comprehensive brain autopsies. The neuropathologic abnormalities assessed were Alzheimer disease (AD) neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis, microinfarcts, and low brain weight. Associations with screening tests for cognitive impairment were examined.Results: Neuropathologic abnormalities occurred at levels ranging from 9.7% to 43%, and were independently associated with cognitive impairment in both studies. Neocortical LBs and AD changes were more frequent among the predominantly Caucasian NS women, while microinfarcts were more common in the Japanese American HAAS men. Comorbidity was usual and very strongly associated with cognitive impairment. Apparent cognitive resilience (no cognitive impairment despite Braak stage V) was strongly associated with minimal or no comorbid abnormalities, with fewer neocortical AD lesions, and weakly with longer interval between final testing and autopsy.Conclusions: Total burden of comorbid neuropathologic abnormalities, rather than any single lesion type, was the most relevant determinant of cognitive impairment in both cohorts, often despite clinical diagnosis of only AD. These findings emphasize challenges to dementia pathogenesis and intervention research and to accurate diagnoses during life. A 1997 Nun Study (NS) report demonstrated a powerful effect on cognitive function of comorbid brain infarcts and Alzheimer disease (AD) neuropathologic changes, reporting an odds ratio (OR) of 20.7 for dementia in participants with both high levels of AD neuropathologic changes and cerebral infarcts.1 A 2002 report of 285 autopsied participants in the Honolulu-Asia Aging Study (HAAS) provided a comprehensive description of 4 major neuropathologic abnormalities, each robustly associated with late-life cognitive impairment: AD neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis (HS), and microinfarcts.2 Subsequent HAAS analyses demonstrated that generalized brain atrophy may occur independently, as a fifth common abnormality associated with cognitive impairment.3,4 Extensive analyses using autopsy and clinical data have further documented both the multiplicity of neuropathologic abnormalities associated with late-life dementia and the complex relationships between them. [5][6][7][8][9][10][11][12] Indeed, the high frequency of neuropathologic comorbidity in older persons with dementia has become widely appreciated around the globe. [13][14][15][16][17][18][19][20][21] In 2013, the first 22 brain autopsies from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were reported. 22 All had been diagnosed during life with AD dementia or AD-type mild cogniti...

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Background: Alzheimer disease, cerebral vascular brain injury, and isocortical Lewy body disease (LBD) are the major contributors to dementia in community-and population-based studies.Objective: To estimate the prevalence of clinically silent forms of these diseases in cognitively normal (CN) adults.

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We report on a test to assess the dynamic brain function at high temporal resolution using magnetoencephalography (MEG) for 45-60 s. After fitting an autoregressive integrative moving average (ARIMA) model and taking the stationary residuals, all pairwise, zero-lag, partial cross-correlations P CC 0 ij and their z-transforms z 0 ij between i and j sensors were calculated, providing estimates of the strength and sign (positive, negative) of direct synchronous coupling at 1 ms temporal resolution. We found that subsets of z 0 ij successfully classified individual subjects to their respective groups (multiple sclerosis, Alzheimer's disease, schizophrenia, Sjögren's syndrome, chronic alcoholism, facial pain, healthy controls) and gave excellent external cross-validation results..

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The concentrations of fourteen neurochemicals associated with metabolism, neurotransmission, antioxidant capacity, and cellular structure were measured noninvasively from two distinct brain regions using 1H magnetic resonance spectroscopy. Seventeen young adults (age 19 – 22 years) and sixteen cognitively normal older adults (age 70 – 88 years) were scanned. To increase sensitivity and specificity, 1H magnetic resonance spectra were obtained at the ultra-high field of 7 T and at ultra-short echo time. The concentrations of neurochemicals were determined using water as an internal reference and accounting for gray matter, white matter, and cerebrospinal fluid content of the volume of interest. In the posterior cingulate cortex (PCC), the concentrations of neurochemicals associated with energy (i.e., creatine plus phosphocreatine), membrane turnover (i.e., choline containing compounds), and gliosis (i.e., myo-inositol) were higher in the older adults while the concentrations of N-acetylaspartylglutamate (NAAG) and phosphorylethanolamine (PE) were lower. In the occipital cortex (OCC), the concentration of N-acetylaspartate (NAA), a marker of neuronal viability, concentrations of the neurotransmitters Glu and NAAG, antioxidant ascorbate (Asc), and PE were lower in the older adults while the concentration of choline containing compounds was higher. Altogether, these findings shed light on how the human brain ages differently depending on region.

The resonances originating from proteins underlie those of metabolites in brain H nuclear magnetic resonance (NMR) spectra. These resonances have different physical properties from those of metabolites, such as shorter T and T relaxation time constants. The age dependence of the macromolecular pattern and content in the human brain was investigated with a focus on adults over 66 years of age using ultrahigh-field in vivo magnetic resonance spectroscopy. Eighteen young and 23 cognitively normal older adults were studied at 7 T. Metabolite spectra were acquired in the occipital cortex and the posterior cingulate cortex with single-voxel stimulated echo acquisition mode (STEAM) spectroscopy in 14 young and 20 older adults. Macromolecular spectra were acquired in the occipital cortex using an inversion recovery STEAM sequence in four young and three older adults. The macromolecular pattern was apparent over the 0.5-4.5-ppm range in the inversion recovery spectra and the 0.5-2-ppm range in the metabolite spectra. Macromolecular content was quantified from metabolite spectra using LCModel and from inversion recovery spectra using integration. Age-associated differences in the macromolecular pattern were apparent via both types of spectra, with the largest difference observed for the 1.7- and 2-ppm macromolecular resonances. A higher macromolecular content was observed in the older adults for both brain regions. Age-specific macromolecular spectra are needed when comparing metabolite spectra from subjects of differing ages because of age-associated differences in macromolecular pattern. Age-associated pattern and content differences may provide information about the aging process.